Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology

Abstract

Background: Various pathways have been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFPEF). Inflammation in response to comorbid conditions, such as hypertension and diabetes, may play a proportionally larger role in HFPEF as compared to HF with reduced ejection fraction (HFREF).

Methods and results: This study investigated inflammation mediated by the tumor necrosis factor-alpha (TNFα) axis in community-based cohorts of HFPEF patients (n = 100), HFREF patients (n = 100) and healthy controls (n = 50). Enzyme-linked immunosorbent assays were used to investigate levels of TNFα, its two receptors (TNFR1 and TNFR2), and a non-TNFα cytokine, interleukin-6 (IL-6), in plasma derived from peripheral blood samples. Plasma levels of TNFα and TNFR1 were significantly elevated in HFPEF relative to controls, while levels of TNFR2 were significantly higher in HFPEF than both controls and HFREF. TNFα, TNFR1 and TNFR2 were each significantly associated with at least two of the following: age, estimated glomerular filtration rate, hypertension, diabetes, smoking, peripheral vascular disease or history of atrial fibrillation. TNFR2 levels were also significantly associated with increasing grade of diastolic dysfunction and severity of symptoms in HFPEF.

Conclusions: Inflammation mediated through TNFα and its receptors, TNFR1 and TNFR2, may represent an important component of a comorbidity-induced inflammatory response that partially drives the pathophysiology of HFPEF.

Figure 1. Circulating inflammatory markers in healthy control (HC), HFPEF (PEF) and HFREF (REF).

Box and whisker plots show the relative distributions of TNF-α (A), TNFR1 (B), TNFR2 (C) and IL-6 (D) levels. * P<0.05, *** P<0.001 for Kruskal-Wallis Test with pairwise comparisons.

Figure 2. Associations of TNFR1 and TNFR2 with disease parameters.

Forest plots show odds ratios and 95% confidence intervals (95%CI) for TNFR1 (R1) or TNFR2 (R2) as predictors of increasing grade of diastolic dysfunction or NYHA class in HFPEF (PEF) or HFREF (REF) (A). Scatterplots show average E/e' ratio as a function of TNFR1 (B) or TNFR2 (C) in HFPEF.

Figure 3. Angiotensin-converting enzyme 2 (ACE2) activity in HFPEF, and comparison with disease parameters.

Box and whisker plots compare the distribution of plasma ACE2 activity in healthy control (HC) and HFPEF (PEF) (A). Forest plots show odds ratio and 95% confidence interval (95%CI) for ACE2 as predictor of increasing grade of diastolic dysfunction or NYHA class in HFPEF (B). * P<0.05 for Mann Whitney U test.